The present invention relates to a process for the preparation of gabapentin.
Gabapentin, namely 1-aminomethyl-1-cyclohexaneacetic acid, of formula (I) 
a medicament widely used in the treatment of pathologies of Central Nervous System, is disclosed in U.S. Pat. Nos. 4,024,175 and 4,087,544.
Said patents disclose the hydrate hydrochloride salt, while gabapentin hydrate sodium salt is disclosed in U.S. Pat. No. 4,894,476.
A variety of processes for the preparation of gabapentin are known: for example, the conversion of 1,1-cyclohaxanediacetic acid to gabapentin by treatment with azides and thermal degradation according to Curtius has been described.
Another known method includes subjecting the corresponding hydroxamic acid to Lossen rearrangement.
U.S. Pat. No. 5,091,567 discloses a process based on Michael condensation between cyclohexanone and a phosphonoacetic acid ester, the subsequent reaction with nitromethane to give the cyclohexylideneacetic acid ester, the reduction of the nitro group to give a mixture of gabapentin ester and of the corresponding lactam (2-aza-spiro[4.5]decan-3-one), the acid hydrolysis of the latter and the treatment of the gabapentin salt with ion exchange resins.
An improved process has now been found, wherein the phosphonoacetic acid ester is replaced with the more convenient acetonitrile, and wherein the formation of a mixture of gabapentin and corresponding lactam is avoided.
The process of the invention comprises:
a) reduction of (1-nitromethyl-cyclohexyl)acetonitrile of formula (II) 
xe2x80x83to give 3-imino-2-aza-spiro[4.5]decan-2-ol of formula (III) 
b) transformation of compound (III), by alkali treatment, into 2-hydroxy-2-aza-spiro[4.5]decan-3-one of formula (IV) 
c) reduction of compound (IV) to give 2-aza-spiro[4.5]decan-3-one of formula (V) 
d) hydrolysis of compound (V) to gabapentin.
The invention further relates to the novel intermediates of formulae (III) and (IV), which are up to now unknown.
The compound of formula (II) was disclosed in WO 99/31075 and can be prepared by reaction of cyclohexylideneacetonitrile and nitromethane in a solvent such as dimethylsulfoxide in the presence of bases, for example alkali carbonates.
Cyclohexylideneacetonitrile can in turn be obtained by reacting cyclohexanone and acetonitrile according to what described in Synthesis 629, 1977 and in J.Org.Chem., 4640, 1979.
Step a) is preferably effected by catalytic hydrogenation, for example over palladium, using solvents selected from alcohols, ethers, esters, hydrocarbons, halogenated hydrocarbons. Preferred solvents are methanol or ethanol.
Compound (III) is converted into compound (IV) by treatment with bases, such as aqueous alkali hydroxides.
Step c) is carried out by catalytic hydrogenation, preferably using a nickel catalyst and an alcohol as solvent.
Finally, hydrolysis of compound (V) to Gabapentin is effected according to known methods, for example by acid hydrolysis.